3-amino-1-phenyl-1h,5h,-benzo-2,4-thiazepines

ABSTRACT

This invention provides new compounds of formula I, ##STR1## wherein R 1  and R 2  are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or lower alkyl, 
     R 3  is hydrogen, lower alkyl, lower hydroxyalkyl, or phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is unsubstituted or mono-substituted, or independently di-substituted, by halogen, lower alkyl, lower alkoxy, amino, lower alkylamino or di(lower alkyl)amino, and 
     R 4  is hydrogen, lower alkyl or lower hydroxyalkyl, 
     Useful as anti-arrhythmics and anti-depressants.

The present invention reltes to benzo-3,4-thiazepines.

The present invention provides new compounds of formula I, ##STR2##wherein R₁ and R₂ are independently hydrogen, halogen, trifluoromethyl,lower alkoxy or lower alkyl,

R₃ is hydrogen, lower alkyl, lower hydroxyalkyl, or phenylalkyl of 7 to10 carbon atoms, wherein the phenyl ring is unsubstituted ormono-substituted, or independently di-substituted by halogen, loweralkyl, lower alkoxy, amino, lower alkylamino or di(lower alkyl)amino,and

R₄ is hydrogen, lower alkyl or lower hydroxyalkyl.

R₁ is preferably in the 7 or 8 position, especially the 8 position. R₁is preferably hydrogen, or halogen.

R₂ is conveniently in the ortho or para position. R₂ is, however,preferably hydrogen.

R₃ is conveniently substituted or unsubstituted phenylalkyl. When thephenyl ring of R₃ is substituted it is preferably mono-substituted. Whenthe phenyl ring is di-substituted, the substituents are preferably thesame and are preferably other than amino. One substituent in the phenylring is preferably in the para position.

It will be appreciated that when R₄ is hydrogen, the compounds alsoexist in the following tautomeric form of formula Ia, ##STR3## WHEREINR₁, R₂ and R₃ are as defined above.

Halogen is fluorine, bromine or preferaby chlorine.

"Lower alkyl, lower hydroxyalkyl or lower alkoxy" as used hereinpreferably refers to radicals of up to 4 carbon atoms, especially 1 or 2carbon atoms. However, lower hydroxyalkyl especially refers to radicalscontaining 2 or 3 carbon atoms. Additionally, R₃ and R₄ when lower alkylespecially have 1 to 3 carbon atoms.

The present invention furthermore provides a process for the productionof a compound of formula I as defined above which comprisesintramolecularly cyclizing a compound of formula II, ##STR4## wherein R₁to R₄ are as defined above.

The reaction may be carried out in conventional manner for suchintramolecular cyclizations. For example, the reaction may be carriedout in the presence of a strong acid, for example hydrochloric acid,trifluoroacetic acid, or benzenesulphonic acid. The reaction may beeffected in the presence of water. Conveniently an organic solvent isused, e.g. glacial acetic acid, a lower alcohol such as ethanol, orpreferably an aliphatic ketone such as acetone. A suitable temperatureis from 20° to 150° C., preferably room temperature.

A compound of formula II, wherein R₄ is hydrogen, may be produced byreacting a compound of formula III, ##STR5## wherein R₁ and R₂ are asdefined above, with an amine of formula R₃ NH₂, wherein R₃ is as definedabove, in conventional manner.

Alternatively a compound of formula IV,

    s = c = n -- r.sub.3.sup.i                                 iv

wherein R₃ ^(I) is hydrogen, lower alkyl, phenylalkyl of 7 to 10 carbonatoms, wherein the phenyl ring is unsubstituted, or mono-substituted, orindependently di-substituted, by halogen, lower alkyl, lower alkoxy, ordi(lower alkyl) amino, may be reacted in conventional manner with acompound of formula V, ##STR6## wherein R₁, R₂ and R₄ are as definedabove, to produce the corresponding compound of formula II, wherein R₃is R₃ ^(I) as defined above.

A compound of formula III, as defined above, may be produced by reactingin conventional manner carbon disulphide, ethyl chloroformate and acompound of formula V, wherein R₄ is hydrogen.

Insofar as the production of the starting materials is not particularlydescribed, these compounds are known or may be produced and purified inaccordance with known processes, or in a manner analogous to theprocesses described herein e.g. in the Examples where appropriate usingsuitable protecting groups.

The above mentioned compounds may be isolated and purified usingconventional techniques. Free base forms of the compounds of formula Imay be converted into acid addition salt forms in conventional mannerand vice versa. A suitable salt is the hydrobromide or hydrochloridesalt.

In the following examples all temperatures are uncorrected and are indegrees Centigrade.

Melting points refer to the hydrochloride form with decomposition unlessstated otherwise, e.g.

1. no decomposition

2. hydrobromide salt

3. hydrochloride salt demi-hydrate.

EXAMPLE 18-Chloro-3-phenylethylamino-1-phenyl-1H,5H-benzo-2,4-thiazepine

a. A solution of1-(4-chloro-2-(α-hydroxybenzyl)-benzyl)-3-phenethyl-thiourea (17 g;0.041 mole) in dry acetone (400 ml) and 85 ml saturated ethanolichydrogen chloride was stirred at room temperature for 20 hours. Thereaction mixture was filtered. The filtrate was evaporated to yield thetitle compound in hydrochloride form (M.Pt. 120° decomp.).

The starting material was obtained as follows:

b. 2-aminomethyl-5-chlorobenzhydrol (10 g; 0.04 mole) in 100 ml methanoland 2 ml triethylamine was treated dropwise with a solution of phenethylisothiocyanate (8.6 g; 0.053 mole) in 25 ml of methanol. After 16 hoursat room temperature the reaction mixture was evaporated and the residuewas extracted with petroleum ether. The residual oil was recrystallizedfrom diisopropyl ether to yield1-(4-chloro-2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea as a whitepowder (M.Pt. 97° -- 101° ).

In analogous manner to that described in Example 1a the followingcompounds of formula I are produced wherein R₄ is hydrogen, and:

    __________________________________________________________________________    Ex. No.                                                                            R.sub.1                                                                            R.sub.2                                                                            R.sub.3       M.Pt.                                            __________________________________________________________________________     2)  8-Cl H    CH.sub.3      204-206°                                   3)  H    H    CH.sub.3      194-195° .sup.1)                           4)  H    H    C.sub.2 H.sub.5                                                                             156-160°                                   5)  H    H    isoC.sub.3 H.sub.7                                                                          197-199°                                   6)  8-Cl H    C.sub.2 H.sub.5                                                                             187-188° .sup.1)                           7)  8-Cl H    isoC.sub.3 H.sub.7                                                                          194-195° .sup.1)                           8)  7-Cl H    CH.sub.3      192-193°                                   9)  H    H                                                                                   ##STR7##     175-177°                                  10)  7-Cl H    isoC.sub.3 H.sub.7                                                                          166-169° .sup.1)3)                        11)  H    H                                                                                   ##STR8##     172-174° .sup.1)                          12)  H    H                                                                                   ##STR9##     124-127° .sup.1)                          13)  H    H                                                                                   ##STR10##    171-174° .sup.1)                          14)  H    H                                                                                   ##STR11##    137-140° .sup.1)                          15)  H    H                                                                                   ##STR12##    175-178°                                  16)  H    H                                                                                   ##STR13##                                                     17)  H    H                                                                                   ##STR14##                                                     18)  7-Cl H                                                                                   ##STR15##                                                     19)  H    H                                                                                   ##STR16##                                                     20)  7-Cl H                                                                                   ##STR17##                                                     21)  7-Cl H                                                                                   ##STR18##                                                     22)  H    H                                                                                   ##STR19##                                                     23)  H    4'-Cl                                                                               ##STR20##                                                     24)  8-Cl H                                                                                   ##STR21##                                                     25)  H    4'-Cl                                                                               ##STR22##                                                     26)  7-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                27)  8-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                28)  7-CH.sub.3                                                                         H                                                                                   ##STR23##                                                     29)  8-CH.sub.3                                                                         H                                                                                   ##STR24##                                                     30)  H    H    H                                                              31)  8-Cl H    H                                                              32)  8-CH.sub.3                                                                         H    CH.sub.3                                                       33)  H    2'-Cl                                                                              CH.sub.3                                                       34)  H    4'-CH.sub.3                                                                        CH.sub.3                                                       35)  7-Cl H    C.sub.2 H.sub.5                                                36)  H    H                                                                                   ##STR25##                                                     37)  H    H    [CH.sub.2 ].sub.2 OH                                           38)  H    H    [CH.sub.2 ].sub.3 OH                                           39)  7-Cl H                                                                                   ##STR26##                                                     40)  7-Cl H                                                                                   ##STR27##                                                     41)  8-Cl H                                                                                   ##STR28##                                                     __________________________________________________________________________

In analogous manner to Example 1 the following compounds of formula Iaare prepared, wherein:

    __________________________________________________________________________    Ex. No.                                                                            R.sub.1                                                                            R.sub.2                                                                            R.sub.3 R.sub.4 M.Pt.                                          __________________________________________________________________________    42)  H    H    isoC.sub.3 H.sub.7                                                                    isoC.sub.3 H.sub.7                                                                    226-227°                                43)  H    H    isoC.sub.3 H.sub.7                                                                    CH.sub.3                                                                              226-227°                                44)  8-Cl H    CH.sub.3                                                                              CH.sub.3                                                                              140-145°                                45)  H    H    CH.sub.3                                                                              isoC.sub.3 H.sub.7                                                                    165-166°.sup.3)                         46)  7-Cl H    CH.sub.3                                                                              CH.sub.3                                                                              196-198°                                47)  H    H    CH.sub.3                                                                              CH.sub.3                                                                              189-190°                                48)  H    H    C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                       182-184°                                49)  H    H    n-C.sub.3 H.sub.7                                                                     n-C.sub.3 H.sub.7                                                                     213-216°.sup.1)2)                       50)  8-Cl H    n-C.sub.3 H.sub.7                                                                     n-C.sub.3 H.sub.7                                                                     133-135°.sup.1)3)                       51)  H    H                                                                                   ##STR29##                                                                            CH.sub.3                                                                              191-195°.sup.1)2)                       52)  H    H    CH.sub.3                                                                              CH.sub.3                                               53)  8-CH.sub.3                                                                         H    CH.sub.3                                                                              CH.sub.3                                               54)  H    2'-Cl                                                                              CH.sub.3                                                                              CH.sub.3                                               55)  H    4'-CH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3                                               56)  H    H    CH.sub.3                                                                              [CH.sub.2 ].sub. 2 OH                                  57)  H    H    [CH.sub.2 ].sub.2 OH                                                                  CH.sub.3                                               58)  H    H    C.sub.2 H.sub.5                                                                       CH.sub.3                                               59)  7-Cl H    C.sub.2 H.sub.5                                                                       CH.sub.3                                               60)  8-Cl H    C.sub.2 H.sub.5                                                                       CH.sub.3                                               61)  H    H    [CH.sub.2 ].sub.2 OH                                                                  CH.sub.3                                               62)  7-Cl H    [CH.sub.2 ].sub.2 OH                                                                  CH.sub.3                                               63)  8-Cl H    [CH.sub.2 ].sub.2 OH                                                                  CH.sub.3                                               __________________________________________________________________________

EXAMPLE 64 1-(2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea (startingmaterial for Example 9)

a. A solution of 1 g of 2-aminomethylbenzhydrol hydrochloride in 4 ml ofwater is added dropwise to a mixture of 0.32 g of sodium hydroxide in 2ml water and 0.25 ml carbon disulphide cooled in ice. The mixture ismaintained at room temperature for 30 minutes and then on a steam bathfor 30 minutes. 0.28 ml of ethyl chloroformate is added to the cooledreaction mixture, which is stirred at room temperature overnight. Thesolution is worked up in conventional manner to give1-(2-(α-hydroxybenzyl)benzyl)-isothiocyanate as an oil.

b. 500 mg of 1-(2-(α-hydroxybenzyl)benzyl)-isothiocyanate and 240 mg ofphenylethyl-amine in 10 ml of benzene are maintained for 4.5 days atroom temperature, and worked up in conventional manner to yield thetitle compound in free base form; M.Pt. 117° - 119°.

The compounds of formula I exhibit pharmacological activity. Inparticular, the compounds of formula I exhibit anti-arrhythmic activityas indicated in standard tests, for example (i) by an anti-arrhythmiceffect in the chloroform arrhythmia test in the mouse according to themethod of J. W. Lawson [J. Pharmac. exp. Ther., 160, 22-31 (1968)] onadministration i.p. of 5 to 50 mg/kg animal body weight of thecompounds, and (ii) by a prolongation of the functional refractoryperiod of the isolated albino guinea pig left atria according to themethod of N. Reuter, E. Haag and U. Haller [Arch. Pharmac., 268,323-333, (1971)] using a bath concentration of 1 to 25 μM of thecompounds.

The compounds are therefore useful as antiarrhythmic agents for thetreatment of heart rhythm disorders.

For the above mentioned use the dosage will, of course, vary dependingon the compound employed, mode of administration and therapy desired.However, in general, satisfactory results are obtained when administeredat a daily dosage of from 0.01 mg to about 50 mg per kg animal bodyweight, conveniently given in divided doses 2 to 4 times a day or insustained release form. For the larger mammal, the total daily dosage isin the range from about 1 to about 50 mg, and dosage forms suitable fororal administration comprise from about 0.2 mg to about 25 mg of thecompounds admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I additionally exhibit anti-depressant activityas indicated in standard tests, for example, the tetrabenazineantagonism test in the mouse on administration i.p. of form 1 to 50mg/kg animal body weight of the compounds.

The compounds are further useful for use as antidepressant agents forthe treatment of exogeneous and endogeneous depressions.

For the above mentioned use the dosage will, of course, vary dependingon the compound employed, mode of administration and therapy desired.However, in general, satisfactory results are obtained when administeredat a daily dosage of from 0.01 mg to about 50 mg per kg animal bodyweight, conveniently given in divided doses 2 to 4 times a day or insustained release form. For the larger mammal, the total daily dosage isin the range from about 1 to about 100 mg, and dosage forms suitable fororal administration comprise from about 0.2 mg to about 50 mg of thecompounds admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I may be administered in pharmaceuticallyacceptable acid addition salt form. Such acid addition salt formsexhibit the same order of activity as the free base forms and arereadily prepared in conventional manner. The present invention alsoprovides a pharmacological composition comprising a compound of formulaI, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutical carrier or diluent. Suchcompositions may be in the form of, for example, a solution or a table.

In one group of compounds R₁ and R₂ are independently hydrogen, halogenor lower alkyl and R₃ is lower alkyl or hydroxyalkyl. In a sub-group R₄is hydrogen. In another sub-group R₄ is lower alkyl or hydroxyalkyl.

In a preferred group of compounds R₃ is R₃ ^(I) as defined above, andespecially R₄ is hydrogen.

The Example 1 compound is the preferred compound.

I claim:
 1. A compound of formula I, ##STR30## wherein R₁ and R₂ areindependently hydrogen, halogen, trifluoromethyl, lower alkoxy or loweralkyl,R₃ is hydrogen, lower alkyl, lower hydroxyalkyl, or phenylalkyl of7 to 10 carbon atoms, wherein the phenyl ring is unsubstituted ormono-substituted, or independently di-substituted, by halogen, loweralkyl, lower alkoxy, amino, lower alkylamino or di(lower alkyl)amino,and R₄ is hydrogen,in free base form or in pharmaceutically acceptableacid addition salt form thereof.
 2. A pharmaceutical composition usefulin treating depression or heart rhythm disorder comprising atherapeutically effective amount of a compound of claim 1 in associationwith a pharmaceutical carrier or diluent.
 3. A method of treatingdepressions in animals which comprises administering a therapeuticallyeffective amount of a compound of claim 1 to an animal in need of suchtreatment.
 4. A method of treating heart rhythm disorders in animalswhich comprises administering a therapeutically effective amount of acompound of claim 1 to an animal in need of such treatment.
 5. Acompound of claim 1, wherein R₁ and R₂ independently are hydrogen, loweralkyl or halogen, and R₃ is lower alkyl or hydroxyalkyl.
 6. A compoundof claim 1 which is8-chloro-3-phenylethylamino-1-phenyl-1H,5H-benzo-2,4-thiazepine.
 7. Acompound of the formula ##STR31## wherein R₁ and R₂ are independentlyhydrogen, halogen, trifluoromethyl, lower alkoxy or lower alkyl,R₃ ishydrogen, lower alkyl, or phenylalkyl of 7 to 10 carbon atoms, whereinthe phenyl ring is unsubstituted or mono-substituted, or independentlydi-substituted, by halogen, lower alkyl, lower alkoxy, or di (loweralkyl)amino, and R₄ is hydrogen, lower alkyl or lower hydroxyalkyl,infree base form or in pharmaceutically acceptable acid addition salt formthereof.
 8. A pharmaceutical composition useful in treating depressionor heart rhythm disorder comprising a therapeutically effective amountof a compound of claim 7 in association with a pharmaceutical carrier ordiluent.
 9. A method of treating depressions in animals which comprisesadministering a therapeutically effective amount of a compound of claim7 to an animal in need of such treatment.
 10. A method of treating heartrhythm disorders in animals which comprises administering atherapeutically effective amount of a compound of claim 7 to an animalin need of such treatment.
 11. A compound of claim 7, wherein R₄ ishydrogen.
 12. A compound of claim 7, wherein R₄ is lower alkyl or lowerhydroxyalkyl.
 13. A compound of claim 1, wherein R₁, R₂ and R₃respectively are 8-Cl, H and CH₃.
 14. A compound of claim 1, wherein R₁,R₂ and R₃ respectively are H, H, and CH₃.
 15. A compound of claim 1,wherein R₁, R₂ and R₃ respectively are H, H and C₂ H₅.
 16. A compound ofclaim 1, wherein R₁, R₂ and R₃ respectively are H, H and isoC₃ H₇.
 17. Acompound of claim 1, wherein R₁, R₂ and R₃ respectively are 8-Cl, H andC₂ H₅.
 18. A compound of claim 1, wherein R₁, R₂ and R₃ respectively are8-Cl, H and isoC₃ H₇.
 19. A compound of claim 1, wherein R₁, R₂ and R₃respectively are 7-Cl, H and CH₃.
 20. A compound of claim 1, wherein R₁,R₂ and R₃ respectively are H, H and ##STR32##
 21. A compound of claim 1,wherein R₁, R₂ and R₃ respectively are 7-Cl, H and isoC₃ H₇.
 22. Acompound of claim 1, wherein R₁, R₂ and R₃ respectively are H, H and##STR33##
 23. A compound of claim 1, wherein R₁, R₂ and R₃ respectivelyare H, H and ##STR34##
 24. A compound of claim 1, wherein R₁, R₂ and R₃respectively are H, H and ##STR35##
 25. A compound of claim 1, whereinR₁, R₂ and R₃ respectively are H, H and ##STR36##
 26. A compound ofclaim 1, wherein R₁, R₂ and R₃ respectively are H, H and ##STR37##
 27. Acompound of claim 1, wherein R₁, R₂ and R₃ respectively are H, H and##STR38##
 28. A compound of claim 1, wherein R₁, R₂ and R₃ respectivelyare H, H and ##STR39##
 29. A compound of claim 1, wherein R₁, R₂ and R₃respectively are 7-Cl, H and ##STR40##
 30. A compound of claim 1,wherein R₁, R₂ and R₃ respectively are H, H and ##STR41##
 31. A compoundof claim 1, wherein R₁, R₂ and R₃ respectively are 7-Cl, H and ##STR42##32. A compound of claim 1, wherein R₁, R₂ and R₃ respectively are 7-Cl,H and ##STR43##
 33. A compound of claim 1, wherein R₁, R₂ and R₃respectively are H, H and ##STR44##
 34. A compound of claim 1, whereinR₁, R₂ and R₃ respectively are H, 4'-Cl and ##STR45##
 35. A compound ofclaim 1, wherein R₁, R₂ and R₃ respectively are 8-Cl, H and ##STR46##36. A compound of claim 1, wherein R₁, R₂ and R₃ respectively are H,4'-Cl and ##STR47##
 37. A compound of claim 1, wherein R₁, R₂ and R₃respectively are 7-CH₃, H and C₂ H₅.
 38. A compound of claim 1, whereinR₁, R₂ and R₃ respectively are 8-CH₃, H and C₂ H₅.
 39. A compound ofclaim 1, wherein R₁, R₂ and R₃ respectively are 7-CH₃, H and ##STR48##40. A compound of claim 1, wherein R₁, R₂ and R₃ respectively are 8-CH₃,H and ##STR49##
 41. A compound of claim 1, wherein R₁, R₂ and R₃respectively are H, H and H.
 42. A compound of claim 1, wherein R₁, R₂and R₃ respectively are 8-Cl, H and H.
 43. A compound of claim 1,wherein R₁, R₂ and R₃ respectively are 8-CH₃, H and CH₃.
 44. A compoundof claim 1, wherein R₁, R₂ and R₃ respectively are H, 2'-Cl and CH₃. 45.A compound of claim 1, wherein R₁, R₂ and R₃ respectively are H, 4'-CH₃and CH₃.
 46. A compound of claim 1, wherein R₁, R₂ and R₃ respectivelyare 7-Cl, H and C₂ H₅.
 47. A compound of claim 1, wherein R₁, R₂ and R₃respectively are H, H and ##STR50##
 48. A compound of claim 1, whereinR₁, R₂ and R₃ respectively are H, H and [CH₂ ]₂ OH.
 49. A compound ofclaim 1, wherein R₁, R₂ and R₃ respectively are H, H and [CH₂ ]₃ OH. 50.A compound of claim 1, wherein R₁, R₂ and R₃ respectively are 7-Cl, Hand ##STR51##
 51. A compound of claim 1, wherein R₁, R₂ and R₃respectively are 7-Cl, H and ##STR52##
 52. A compound of claim 1,wherein R₁, R₂ and R₃ respectively are 8-Cl, H and ##STR53##
 53. Acompound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are H, H,isoC₃ H₆₇ and isoC₃ H₇.
 54. A compound of claim 7, wherein R₁, R₂, R₃and R₄ respectively are H, H, isoC₃ H₇ and CH₃.
 55. A compound of claim7, wherein R₁, R₂, R₃ and R₄ respectively are 8-Cl, H, CH₃ and CH₃. 56.A compound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are H, H,CH₃ and isoC₃ H₇.
 57. A compound of claim 7, wherein R₁, R₂, R₃ and R₄respectively are 7-Cl, H, CH₃ and CH₃.
 58. A compound of claim 7,wherein R₁, R₂, R₃ and R₄ respectively are H, H, CH₃ and CH₃.
 59. Acompound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are H, H, C₂H₅ and C₂ H₅.
 60. A compound of claim 7, wherein R₁, R₂, R₃ and R₄respectively are H, H, n-C₃ H₇ and n-C₃ H₇.
 61. A compound of claim 7,wherein R₁, R₂, R₃ and R₄ respectively ae 8-Cl, H, n-C₃ H₇ and n-C₃ H₇.62. A compound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are H,H, ##STR54## and CH₃.
 63. A compound of claim 7, wherein R₁, R₂, R₃ andR₄ respectively are 8-CH₃, H, CH₃, and CH₃.
 64. A compound of claim 7,wherein R₁, R₂, R₃ and R₄ respectively are H, 2'-Cl, CH₃ and CH₃.
 65. Acompound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are H,4'-CH₃, CH₃ and CH₃.
 66. A compound of claim 7, wherein R₁, R₂, R₃ andR₄ respectively are H, H, CH₃ and [CH₂ ]₂ OH.
 67. A compound of claim 7,wherein R₁, R₂, R₃ and R₄ respectively are H, H, C₂ H₅ and CH₃.
 68. Acompound of claim 7, wherein R₁, R₂, R₃ and R₄ respectively are 7-Cl, H,C₂ H₅ and CH₃.
 69. A compound of claim 7, wherein R₁, R₂, R₃ and R₄respectively are 8-Cl, H, C₂ H₅ and CH₃.